JPH06128256A - Imidazopyridine derivative - Google Patents

Abstract

PURPOSE:To provide a compound having angiotensin II antagonistic activity, useful as a preventive or medicine for hypertension, heart failure etc. CONSTITUTION:The compound of formula I [R<1> is CH2OR<3> (R<3> is H or lower alkyl) or (protected) carboxyl; R<2> is (protected) carboxyl or tetrazole], e.g. 2-cyclopropyl-7-hydromethyl-3-[(2'-methoxycarbonylbiphen-4-yl)methyl]-3H- imidazo[4,5-b]pyridine. The compound of the formula I can be obtained by oxidation of a compound of formula II followed by esterification and then condensation to produce a compound of formula III (B is carboxyl-protecting group; Y is eliminable group), which is then hydrolyzed and deprotected.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an imidazopyridine derivative useful as a medicine or a pharmaceutically acceptable salt thereof. More specifically, 2-cyclopropyl-3H-imidazo [4, which has angiotensin II antagonism
5-b] pyridine derivative or a pharmaceutically acceptable salt thereof.

[0002]

BACKGROUND OF THE INVENTION AND PRIOR ART Hypertension is about 2 in Japanese.
Although it is said that 0% is affected, it is a disease with a large number of patients, but the pathophysiology and causes are very diverse,
The current situation is that there are some unclear causes. Cases of transition from hypertension to various brain diseases such as intracerebral hemorrhage and heart diseases such as heart failure,
In many cases, there are serious complications, and appropriate treatment at an early stage is now an important issue.

Currently, as drug treatments for hypertension, drugs having various mechanism of action such as antihypertensive diuretics, β-blockers, calcium antagonists, ACE inhibitors are actually used clinically. Since the pathophysiology and causes of hypertension are extremely diverse, it is difficult at this stage to predominantly control all types of hypertension. From the viewpoint of safety, for example, β-blockers include cardiac depression, bronchospasm, diuretics include hyperuricemia, electrolyte abnormalities, abnormal glucose metabolism, and calcium antagonists. Atrioventricular block, transient cardiac arrest, etc. may be seen, and further, ACE inhibitors show dry cough and the like. Therefore, drug selection for patients with complications is rather difficult and requires careful attention.

Under these circumstances, there is still a long-felt need for drugs having different types and different mechanisms of action.

Therefore, the present inventors have conducted extensive studies for a compound having an angiotensin II antagonistic activity for many years, and found that the imidazopyridine derivative shown below has an excellent activity.

3H having angiotensin II antagonism
Examples of the imidazo [4,5-b] pyridine-based compound include JP-A-3-236377 and JP-A-3-5480.
JP-A-3-95181 and JP-A-3-106879.
Japanese Patent Laid-Open No. 188076/1989
No., etc., but each has a different structure from the compound of the present invention described later. Furthermore, JP-A-4-22698
No. 2 discloses a 3H-imidazo [4,5-b] pyridine compound, but has a different structure from the present invention.

[0007]

The present invention is an imidazopyridine derivative represented by the following general formula (I) and a pharmacologically acceptable salt thereof.

[0008]

[Chemical 2]

[Wherein R ¹ is the formula —CH ₂ OR ³ (wherein R ^1
3 represents a hydrogen atom or a lower alkyl group) or a carboxyl group which may be protected, and R ² is a carboxyl group which may be protected or a tetrazole group which may be protected. Means ]

In the definition of the above general formula, the lower alkyl group found in the definition of R ³ is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, n-propyl group. Group, isopropyl group, n-butyl group,
sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, isohexyl group, 2-methylpentyl group, 3-methylpentyl group, 1, A 1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 2,3-dimethylbutyl group, a 2-ethylbutyl group, a 3-ethylbutyl group and the like can be mentioned, but of these, a methyl group and an ethyl group are preferable. , N-propyl group and the like.

The optionally protected carboxyl group in the definition of R ¹ and R ² is a free carboxyl group or a lower alkyl group represented by, for example, a methyl group, an ethyl group, 2, Halogenated alkyl groups such as 2,2-trichloroethyl, 2-iodoethyl and trichloromethyl, lower alkanoyloxyalkyl groups such as pivaloyloxymethyl group, 1-acetoxyethyl group and 2-acetoxyethyl group, and 3-phthaldiyl group. And a carboxyl group protected by a heterocyclic group such as Furthermore, various acid amides can also be included in the protected carboxyl group. In short, the protected carboxyl group may be any group as long as it can be decomposed into a carboxylic acid by some means in vivo.

The optionally protected tetrazolyl group in the definition of R ² may be a free tetrazolyl group, or a lower alkyl group represented by, for example, a methyl group, an ethyl group, 2,2,2. -Substituted lower alkyl groups represented by halogenated alkyl groups such as trichloroethyl, 2-iodoethyl, trichloromethyl and triphenylmethyl groups, pivaloyloxymethyl groups, 1
Examples thereof include a lower alkanoyloxyalkyl group such as -acetoxyethyl group and 2-acetoxyethyl group, and a tetrazolyl group protected with a heterocyclic group such as 3-phthalidyl group. In short, if it is a group that can be decomposed in vivo by some means to become a tetrazolyl group,
Any group is acceptable.

The main production methods of the compound of the present invention are shown below.

[0014]Manufacturing method 1 In the general formula (I), R¹ Carboxy protected
A silyl group and R ² Carboxyl protected
When it is a base, it can also be produced by the following method.

[0015]

[Chemical 3]

(In the series of formulas, A and B mean a protecting group for a carboxyl group, and Y represents a leaving group.)

The first step is a method of oxidizing the compound represented by the general formula (II) by a conventional method to obtain the compound represented by the general formula (III). The oxidizing agent is preferably potassium permanganate, and the solvent is preferably water. In addition, favorable results are obtained by proceeding the reaction in the presence of a weak base such as carbonate. The reaction temperature is preferably 80 ° C to 95 ° C.

The second step is the general formula (I) obtained in the first step.
In this method, the compound represented by the general formula (IV) is obtained by esterifying the compound represented by II) by a conventional method. For example, it can be obtained by heating an excess alcohol represented by the general formula (V) in the presence of an acid catalyst such as concentrated sulfuric acid.

In the third step, the compound (IV) obtained in the second step is condensed with the compound represented by the general formula (VI) by a conventional method to obtain the compound represented by the general formula (VII). . The reaction is preferably carried out in the presence of a base, and examples of the base include sodium hydride, lithium hydride, metal alcoholates, tertiary amines and the like, and among these, sodium hydride is most preferable. As the reaction solvent, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, dioxane, acetone, alcohol and the like are preferable.

The compound (VII) obtained in the third step can be hydrolyzed by a conventional method to remove the protective group for the carboxyl group. For example, by heating in a mixed solvent of ethanol and an aqueous solution of sodium hydroxide, the protective group for the carboxyl group can be easily eliminated. A compound in which only one of the protecting groups R ^{1 and} R ² is eliminated can also be obtained depending on the conditions of hydrolysis.

Production Method 2 Of the compounds represented by the general formula (I), R ¹ is of the formula —CH
_A compound which is a group represented by ₂ OH and R ² is a carboxyl group which may be protected can be produced, for example, by the following method.

[0022]

[Chemical 4]

(In the series of formulas, A and Y have the above-mentioned meanings.)

The first step is a step of obtaining the compound represented by the general formula (IX) by reducing the compound (IV) obtained in the second step of the production method 1 by a conventional method. As the reducing agent, any of those usually used can be used, but lithium aluminum hydride or the like is preferable. As the reaction solvent, any solvent that does not participate in the reaction can be used, but preferably an ether solvent such as tetrahydrofuran can be mentioned.

In the second step, the compound (IX) obtained in the first step is condensed with the compound (VI) in the same manner as in the third step of the production method 1 to obtain the compound (X). .

The third step is a method similar to the fourth step of the production method 1 to hydrolyze the compound (X) to obtain the target compound (XI).

Production Method 3 R ¹ is a group represented by the formula —CH ₂ OR ^3a (wherein R ^3a represents a group selected from the above R ³ excluding a hydrogen atom). Sometimes, it can be manufactured by the following method.

[0028]

[Chemical 5]

(In the series of formulas, R ^3a means a group selected from the above R ³ excluding a hydrogen atom.
Y and R ² have the above-mentioned meanings. ) A method of obtaining the target compound represented by the general formula (XII) by reacting the compound (X) obtained in the second step of the production method 2 with a compound represented by the formula R ^3a Y in the presence of a base. . Examples of preferred bases include sodium hydride, lithium hydride,
Examples include metal alcoholates and tertiary amines,
Among these, sodium hydride is most preferable. The reaction solvent can be produced by reacting in an aprotic polar solvent such as dimethylformamide or tetrahydrofuran.

Production Method 4 When R ² is an optionally protected tetrazolyl group, it can be produced by the following method.

[0031]

[Chemical 6]

(In the series of formulas, D means a hydrogen atom or a protecting group for a tetrazolyl group. R ¹ and Y have the above-mentioned meanings.) The first step, the second step or the production method of the production method 1. The compound (XII) obtained in the first step of 2 has the general formula
In this method, the target compound (XIII) is obtained by reacting the compound represented by (XIV) in the same manner as in the second step of Production method 2.

The protective group for the tetrazolyl group can be removed by a conventional method, and examples thereof include a treatment with an acid and a method of heating under reflux in alcohol. Next, in order to describe the effect of the compound of the present invention in detail, experimental examples are shown.

Experimental Example 1. Experimental method Angiotensin II contracture contraction using rabbit aortic strip
Anti-action Male New Zealand White rabbits weighing 2-3 kg were anesthetized with sodium pentobarbital and the thoracic aorta was removed. The aorta is a helical specimen with a width of 1.5 to 2 mm and a length of 15 to 20 ml.
Bicarbonate liquid (Krebs bicarbonate (m
M): NaCl 118.4, KCl 4.7, CaC
_{l 2, 2.0, MgSO 4 ·} 7H 2 O 1.2, NaH
It was suspended in a 10 ml Magnus tank containing CO ₃ 25.0, KH ₂ PO ₄ 1.2, glucose 1.1).
Indomethacin 10 ⁻⁵ M was added to eliminate the influence of prostaglandin. Krebs solution is kept at 37 ℃ and 95%
Bubbled with O ₂ -5% CO ₂ . Strips have an initial tension of 1
After loading g and letting it stand for about 1 hour, 50 mM KCl was added to induce contraction, and after contraction was stabilized, it was washed.
This operation was repeated twice, and the second time was set as 100% contracture. After this, angiotensin II was ^added from 10 ^-10 to 3 ×
It was added cumulatively up to 10 ⁻⁶ and the rightward shift of the dose-response curve was observed. Contraction is an isometric pressure transducer (TB
611T, Nihon Kohden, and carrier amplifier (AP6
It was made to draw on a multi-pen recorder (R-10, Rika Denki) via 20G or AP621G, Nihon Kohden. The potency of an angiotensin II antagonist is calculated by using the Schild's equation, and the pA ₂ value [negative logarithm (−lo) of the concentration of the competitive antagonist such that the dose ratio of the active drug is 2.
g)] was calculated and determined.

2. Experimental Results The results of the compounds of the present invention are shown below.

[0036]

[Table 1]

From the above results, it was revealed that the compound of the present invention has angiotensin II antagonistic action. Therefore, the compound of the present invention is effective as a prophylactic / therapeutic agent for diseases for which angiotensin II antagonism is effective. Specifically, a prophylactic / therapeutic agent for hypertension such as essential hypertension, renal hypertension, renovascular hypertension and malignant hypertension,
Further, it is useful as a preventive / therapeutic agent for heart failure.

When the compound of the present invention is used as these medicines, it may be orally administered as powders, granules, capsules, syrups, etc., or as suppositories, injections, external preparations and drip infusions. It may be administered parenterally. Although the dose varies remarkably depending on the degree of symptoms, age and the like, in oral administration, about 10 mg to 2000 mg, preferably 50 mg to 1000 mg, per day for an adult is usually administered in 1 to several divided doses per day. Further, in the case of administration by injection, it is usually 10 μg / kg to 10 mg / kg, preferably 50 μg per day.
/ Kg to 5 mg / kg.

When formulating, a usual preparation alone is used, and it is manufactured by a conventional method. That is, when preparing a solid preparation for oral use, after adding the excipient of the main drug, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, etc., a tablet by a conventional method, Coated tablets, granules, powders, capsules, etc.

Examples of the excipient include lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose,
Silicon dioxide or the like, as the binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose,
Methylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin, pectin and the like, and examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil and the like. However, as the coloring agent, those that are allowed to be added to pharmaceuticals, as the flavoring agent, cocoa powder, peppermint brain, aromatic acid, peppermint oil, Borneolum, Keihi powder, etc. are used. tablet,
The granules may of course be sugar-coated, gelatin-coated or any other suitable coating, if desired. When preparing an injection, add a pH adjusting agent, a buffer, a stabilizer, a solubilizer, etc. to the main drug as necessary, and prepare a subcutaneous, intramuscular, or intravenous injection by a conventional method.

[0041]

EXAMPLES Examples of the present invention will be given below.
Needless to say, it is not limited to this. Example
Prior to this, an example of production of the starting compound for the compound of the present invention is shown.
You Production example 1 2-Cyclopropyl-7-imidazo [4,5-b] pyri
Gin carboxylic acid

[0042]

[Chemical 7]

2-Cyclopropyl-7-methylimidazo [4,5-b] pyridine 17.3 g (0.1 mol) and sodium carbonate 6.6 g were added with water 550 ml, and the internal temperature was 82 ° C.
24 g of potassium permanganate (0.15
mol) was added in small portions. Then, the mixture was stirred at an internal temperature of 94 ° C. for 1 hour, cooled and filtered, the filtrate was acidified with acetic acid, and the precipitated crystals were collected by filtration. Used for next step without purification. Yield 11.3 g as crude product.

¹ H-NMR CD ₃ OD δ (ppm) 8.38 (d, 1H, J = 5Hz) 7.51 (d, 1H, J = 5Hz) 2.4
0 (m, 1H) 1.14 (m, 4H)

Production Example 2 2-Cyclopropyl-7-imidazo [4,5-b] pyri
Gin carboxylic acid methyl ester

[0046]

[Chemical 8]

Crude 2-cyclopropyl-7-imidazo [4,5-b] pyridinecarboxylic acid 1 obtained in Preparation Example 1
A mixed solution of 48 ml of methanol and 24 g of concentrated sulfuric acid was added to 1.2 g, and the mixture was stirred for 6 hours. The mixture was opened on ice, neutralized with concentrated aqueous ammonia, sodium chloride was added, and the precipitated crystals (7.6 g) were collected by filtration.
This was recrystallized from a mixed solvent of ethyl acetate-methanol-isopropyl ether. Yield 6.1g.

MASS (FAB) 400 (MH
^{+), 211,190 · 1 H-} NMR CD 3 OD δ (ppm) 12.75 (bs, 1H) 8.37 (d, 1H, J = 5Hz) 7.51 (d, 1
H, J = 5Hz) 3.96 (s, 3H) 2.34 (m, 1H) 1.11 (m, 4Hz)

Production Example 3 2-Cyclopropyl-7-hydromethylimidazo [4,4]
5-b] pyridine

[0050]

[Chemical 9]

Lithium aluminum hydride 160
mg was suspended in 5 ml of tetrahydrofuran and the crude 2-cyclopropyl-7-imidazo [4,5-
b] A tetrahydrofuran suspension of 600 mg of pyridine carboxylic acid methyl ester was added dropwise with a pipette. After stirring at room temperature for 2 hours, 0.2 ml of water, 0.2 ml of 15% sodium hydroxide and 0.6 ml of water were sequentially added, and after stirring, Celite,
After adding anhydrous magnesium sulfate, Celite was put on a glass filter, filtered, and washed well with tetrahydrofuran. The filtrate was concentrated, dissolved in chloroform-methanol, and subjected to column chromatography (2-10% ethanol-chloroform). Yield 320 mg. Yield 61
%.

Yield 61% ¹ H-MNR CD ₃ OD δ (ppm) 8.16 (d, 1H, J = 5Hz) 7.14 (d, 1H, J = 5Hz) 5.40 (b
s, 1H) 4.81 (s, 2H) 2.14 (m, 1H) 1.08 (m, 4H)

Example 1 2-Cyclopropyl-7-hydromethyl-3-{(2 '
-Methoxycarbonylbiphen-4-yl) methyl}-
3H-imidazo [4,5-b] pyridine

[0054]

[Chemical 10]

Preparation Example 3 in 68 mg of 60% sodium hydride
A solution of 310 mg of 2-cyclopropyl-7-hydroxymethylimidazo [4,5-b] pyridine obtained in 1 in 15 ml of dimethylformamide was added dropwise at room temperature. After stirring for 15 minutes, the mixture was ice-cooled and a solution of 590 mg of 4'-bromo-2-biphenylcarboxylic acid methyl ester in 7 ml of dimethylformamide was added dropwise. After stirring at room temperature for 20 minutes, an aqueous solution of ammonium chloride was added while cold, and saline and ethyl acetate were added to separate the layers. The organic layer was washed twice more with water, dried over anhydrous magnesium sulfate, and concentrated. 770 mg of the residue was subjected to column chromatography. Elution was performed with 2-5% ethanol-1% ammonia-methanol-chloroform. Yield 210mg
did.

Yield 31% MASS (FAB) 400 (MH +), 211, 1
90 ・¹H-NMR CD₃ OD δ (ppm) 12.75 (bs, 1H) 8.37 (d, 1H, J = 5Hz) 7.51 (d, 1)
H, J = 5Hz) 3.96 (s, 3H) 2.34 (m, 1H) 1.11 (m, 4Hz) Example 2 3-{(2'-carboxybiphen-4-yl) meth
Ru} -2-cyclopropyl-7-hydroxymethyl-3
H-imidazo [4,5-b] pyridine

[0057]

[Chemical 11]

2-Cyclopropyl-obtained in Preparation Example
To 200 mg of 7-hydroxymethyl-3-{(2'-methoxycarbonylbiphen-4-yl) methyl} -3H-imidazo [4,5-b] pyridine, 5 ml of ethanol was added and dissolved, and 2.5 ml of 7% was added. Aqueous sodium hydroxide solution was added and stirred for 40 minutes. The reaction solution was concentrated to about 1 ml, water was added, 0.4 ml of acetic acid was added, and the precipitated crystals were collected by filtration.
This was dissolved in 10 ml of ethanol with heating, 10 ml of water was added and the mixture was allowed to cool, and the precipitated crystals were collected by filtration. Yield 120 mg.

-Yield 63% -Molecular formula C ₂₄ H ₂₁ N ₃ O-MASS (FAB) 400 (MH +), 211, 1
90 ¹ H-NMR CD ₃ OD δ (ppm) 8.30 (d, 1H, J = 5Hz) 7.77 (d, 1H, J = 8Hz) 7.5
2 (t, 1H, J = 8Hz) 7.44 to 7.38 (m, 2H) 7.33 (d, 1H, J = 8Hz) 7.29 (d
, 2H, J = 8Hz) 7.33 (d, 1H, J = 8Hz) 7.29 (d, 2H, J = 8Hz) 7.24 (d
, 2H, J = 8Hz) 5.72 (s, 2H) 5.06 (s, 2H) 2.19 (m, 1H) 1.14
(m, 4H) -Elemental analysis CHN (%) calculated as molecular weight 399.45 72.17 5.30 10.52 Experimental 72.11 5.46 10.49

Example 3 2-Cyclopropyl-7-methoxycarbonyl-3-
{(2'-methoxycarbonylbiphen-4-yl) me
Chill} -3H-imidazo [4,5-b] pyridine

[0061]

[Chemical 12]

According to the method of Example 1, it was synthesized from the compound of Production Example 2.

NMR DMSO-d₆ δ (ppm) 8.41 (d, 1H, J = 5Hz) 7.82 (dd, 1H, J = 1Hz, 8Hz) 7.74
 (d, 1H, J = 5Hz) 7.51 (td, 1H, J = 1Hz, 8Hz) 7.40 (td, 1H, J = 1Hz, 8Hz) 7.31 (dd, 1H, J = 1Hz, 8Hz) 7.25 (d, 2H , J = 8Hz) 7.22
(d, 2H, J = 8Hz) 5.69 (s, 2H) 4.05 (s, 3H) 3.62 (s, 3H) 2.03 (m,
1H) 1.36 (m, 2H) 1.10 (m, 2H) Example 4 2-carboxy-3-{(2'-carboxybiphene-
4-yl) methyl} -2-cyclopropyl-3H-imi
Dazo [4,5-b] pyridine

[0064]

[Chemical 13]

According to the method of Example 2, it was synthesized from the compound of Production Example 3.

Molecular formula C ₂₄ H ₁₉ N ₃ O ₄ NMR DMSO-d ₆ δ (ppm) 8.39 (d, 1H, J = 5Hz) 7.71 (dd, 1H, J = 1Hz, 8Hz) 7.59
(d, 1H, J = 5Hz) 7.55 (td, 1H, J = 1Hz, 8Hz) 7.44 (td, 1H, J = 1Hz, 8Hz) 7.34 (dd, 1H, J = 1Hz, 8Hz) 7.29 (s, 4H ) 5.72 (s, 2H) 2.39 (m, 1H) 1.14 (m, 4H) ・ MASS (FAB) 414 (MH +), 211 ・ Elemental analysis As molecular weight 413.43 C (%) H (%) N (%) Calculated 69.72 4.63 10.16 Measured 69.65 4.84 9.96

[Chemical 7]

[Chemical 7]

[Chemical 8]

[Chemical 8]

[Chemical 9]

[Chemical 9]

 ─────────────────────────────────────────────────── --- Continuation of the front page (72) Inventor Hiroki Ishihara 42-10 Midorigaoka, Tsukuba City, Ibaraki Prefecture (72) Inventor Shigeru Soda 1687-21 Ushiku-cho, Ushiku-shi, Ibaraki Prefecture

Claims (4)

[Claims] 1. A compound represented by the general formula (I): [Wherein R ¹ represents a group represented by the formula —CH ₂ OR ³ (wherein R ³ represents a hydrogen atom or a lower alkyl group) or an optionally protected carboxyl group, and R ²
Means an optionally protected carboxyl group or an optionally protected tetrazole group. ] The imidazo pyridine derivative represented by these, or its pharmacologically acceptable salt. 2. An angiotensin II antagonist comprising the imidazopyridine derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 3. A prophylactic / therapeutic agent for hypertension, comprising the imidazopyridine derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 4. A prophylactic / therapeutic agent for heart failure, which comprises the imidazopyridine derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.